Quorum quenching of virulence traits expression in human and plant pathogens by Isoxazolone and its molecular docking studies

Komal S. Salkar; Lakshangy S. Charya; Milind M. Naik; Hari K. Kadam; Vishnu Chari

doi:10.7324/JABB.2025.197114

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Abstract

Inhibiting quorum sensing (QS) to hinder extracellular polymeric substances (EPS) production and biofilm formation in pathogenic bacteria was studied as an efficient alternative for controlling the infections caused by multiple drug resistant (MDR) bacteria. In the present study, the isoxazolone derivative (4-(2-hydroxy-5-methoxybenzylidene)- 3-methylisoxazol-5(4H)-one) was tested for its ability to inhibit EPS production and biofilm formation in human as well as plant pathogenic bacteria. The binding affinity of the derivative to the quorum sensing regulatory proteins (AgrA and LasR) was investigated by carrying out molecular docking studies. The derivative was capable of substantially inhibiting EPS production and biofilm formation in Pseudomonas aeruginosa, Staphylococcus aureus, Erwinia carotovora, and Ralstonia solanacearum at subinhibitory concentrations. Furthermore, molecular docking studies confirmed our results with notable binding affinity −7.5 kcal/mol to transcriptional activator protein LasR and binding affinity −6.8 kcal/mol to AgrA (transcription factor), both controlling expression of virulence factors in P. aeruginosa and S. aureus, respectively. This is a first report that proves that isoxazolone derivatives have quorum quenching potential (QQ) against both human and plant pathogens, which can be applied in medical and agricultural fields.

Keyword: Biofilm formation EPS production Quorum sensing Isoxazolones Quorum quenching Human and plant pathogen

Citation:

Salkar KS, Charya LS, Naik MM, Kadam HK. Quorum quenching of virulence traits expression in human and plant pathogens by Isoxazolone and its molecular docking studies. J App Biol Biotech. 2025. Online First. http://doi.org/10.7324/J ABB.2025.197114

Copyright: Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike license.

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1. Kadam HK, Salkar K, Naik AP, Naik MM, Salgaonkar LN, Charya, L, et al. Silica supported synthesis and quorum quenching ability of isoxazolones against both gram positive and gram negative bacterial pathogens. Chemistry Select. 2021;6(42):11718-28. https://doi.org/10.1002/slct.202101798
2. Hushare VJ, Rajput PR. Synthesis, characterization and antimicrobial activity of some novel isoxazoles. Rasayan J Chem. 2012;5(1):121-6.
3. Arya GC, Kaur K, Jaitak V. Isoxazole derivatives as anticancer agent: a review on synthetic strategies, mechanism of action and SAR studies. Eur J Med Chem. 2021;221:113511. https://doi.org/10.1016/j.ejmech.2021.113511
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5. Yan C, Li X, Zhang G, Zhu Y, Bi J, Hao H, Hou H. Quorum sensing-mediated and growth phase-dependent regulation of metabolic pathways in Hafnia alvei H4. Front Microbiol. 2021;12:567942. https://doi.org/10.3389/fmicb.2021.567942
6. Paluch E, Rewak-Soroczy?ska J, J?drusik I, Mazurkiewicz E, Jermakow KJAM. Prevention of biofilm formation by quorum quenching. Appl Micrbiol Biotechnol. 2020;104:1871-1881. https://doi.org/10.1007/s00253-020-10349-w
7. Wright PP, Ramachandra SS. Quorum sensing and quorum quenching with a focus on cariogenic and periodontopathic oral biofilms. Microorganisms. 2022;10(9):1783. https://doi.org/10.3390/microorganisms10091783
8. Preda VG, S?ndulescu O. Communication is the key: biofilms, quorum sensing, formation and prevention. Discov. 2019;7(3):e100. https://doi.org/10.15190/d.2019.13
9. Zhou L, Zhang Y, Ge Y, Zhu X, Pan J. Regulatory mechanisms and promising applications of quorum sensing-inhibiting agents in control of bacterial biofilm formation. Front Microbiol. 2020;11:589640. https://doi.org/10.3389/fmicb.2020.589640
10. Li T, Mei Y, He B, Sun X, Li J. Reducing quorum sensing-mediated virulence factor expression and biofilm formation in hafnia alvei by using the potential quorum sensing inhibitor L-carvone. Front Microbiol. 2019;9:3324. https://doi.org/10.3389/fmicb.2018.03324
11. Al-Shabib NA, Husain FM, Hassan I, Khan MS, Ahmed F, Qais FA, et al. Biofabrication of zinc oxide nanoparticle from Ochradenus baccatus leaves: broad-spectrum antibiofilm activity, protein binding studies, and in vivo toxicity and stress studies. J Nanomater. 2018;2018:8612158. https://doi.org/10.1155/2018/8612158
12. Richards C, O'Connor N, Jose D, Barrett A, and Regan F. Selection and optimization of protein and carbohydrate assays for the characterization of marine biofouling. Anal Methods. 2020;12(17):2228-36. https://doi.org/10.1039/D0AY00272K
13. Naik MM, Naik SP, Dubey SK, Bhat C, Charya LSJ. Enhanced exopolysaccharide production and biofilm forming ability in methicillin resistant Staphylococcus sciuri isolated from dairy in response to acyl homoserine lactone (AHL). Food Sci Technol. 2018;55:2087-94. https://doi.org/10.1007/s13197-018-3123-0
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15. Nithya C, Begum MF, Pandian SK. Marine bacterial isolates inhibit biofilm formation and disrupt mature biofilms of Pseudomonas aeruginosa PAO1. Appl Microbiol Biotechnol. 2010;88(1):341-58. https://doi.org/10.1007/s00253-010-2777-y
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17. Laskowski RA, Swindells MB. LigPlot+: multiple ligand-protein interaction diagrams for drug discovery. J Chem Inf Model. 2011;51(10):2778-86. https://doi.org/10.1021/ci200227u
18. Myszka K, and Czaczyk K. Characterization of adhesive exopolysaccharide (EPS) produced by Pseudomonas aeruginosa under starvation conditions. Curr Microbiol. 2009;58:541-6. https://doi.org/10.1007/s00284-009-9365-3
19. Mina IR, Jara NP, Criollo JE, Castillo JA. The critical role of biofilms in bacterial vascular plant pathogenesis. Plant Pathol J. 2019;68(8):1439-47. https://doi.org/10.1111/ppa.13073
20. Husain FM, Ahmad I, Al-Thubiani AS, Abulreesh HH, AlHazza IM, Aqil F. Leaf extracts of Mangifera indica L. Inhibit quorum sensing- regulated production of virulence factors and biofilm in test bacteria. Front Microbiol. 2017;8:727. https://doi.org/10.3389/fmicb.2017.00727
21. Fong J, Mortensen KT, Nørskov A, Qvortrup K, Yang L, Tan CH, et al. Itaconimides as novel quorum sensing inhibitors of Pseudomonas aeruginosa. Front Cell Infect. 2019;8:443. https://doi.org/10.3389/fcimb.2018.00443
22. Dincer S, Uslu FM, Delik A. Antibiotic resistance in biofilm. In: Dincer S, Ozdenefe MS, Arkut A, eds. Bacterial Biofilms. London: IntechOpen; 2020. pp. 135-48. https://doi.org/10.5772/intechopen.92388
23. Li Y-H, Tian X. Quorum sensing and bacterial social interactions in biofilms. Sensors. 2012;12(3):2519-38. https://doi.org/10.3390/s120302519
24. Thi MTT, Wibowo D, Rehm BH. Pseudomonas aeruginosa biofilms. Int J Mol Sci. 2020;21(22):8671. https://doi.org/10.3390/ijms21228671
25. Idrees M, Sawant S, Karodia N, Rahman A. Staphylococcus aureus biofilm: morphology, genetics, pathogenesis and treatment strategies. Int J Environ Res Public Health. 2021;18(14):7602. https://doi.org/10.3390/ijerph18147602
26. Joshi JR, Khazanov N, Senderowitz H, Burdman S, Lipsky A, Yedidia I. Plant phenolic volatiles inhibit quorum sensing in pectobacteria and reduce their virulence by potential binding to ExpI and ExpR proteins. Sci Rep. 2016;6(1):38126. https://doi.org/10.1038/srep38126
27. Ha NT, Minh TQ, Hoi PX, Thuy NTT, Furuya N, Long HH. Biological control of potato tuber soft rot using N-acyl-L-homoserine lactone-degrading endophytic bacteria. Curr Sci. 2018;115(10):1921-7. https://doi.org/10.18520/cs/v115/i10/1921-1927
28. Mori Y, Inoue K, Ikeda K, Nakayashiki H, Higashimoto C, Ohnishi K, et al. The vascular plant?pathogenic bacterium R alstonia solanacearum produces biofilms required for its virulence on the surfaces of tomato cells adjacent to intercellular spaces. Mol Plant Pathol. 2016;17(6):890-902. https://doi.org/10.1111/mpp.12335
29. Lowe-Power TM, Khokhani D, Allen C. How Ralstonia solanacearum exploits and thrives in the flowing plant xylem environment. Trends Microbiol. 2018;26(11):929-42. https://doi.org/10.1016/j.tim.2018.06.002
30. Kostylev M, Kim DY, Smalley NE, Salukhe I, Greenberg EP, Dandekar AA. Evolution of the Pseudomonas aeruginosa quorum-sensing hierarchy. Proc Nat Acad Sci. 2019;116(14):7027-32. https://doi.org/10.1073/pnas.1819796116
31. Kushwaha PK, Srivastava KS, Kumari N, Kumar R, Mitra D, Sharon A. Synthesis and anti-HIV activity of a new isoxazole containing disubstituted 1, 2, 4-oxadiazoles analogs. Bioorg Med Chem. 2022;56:116612. https://doi.org/10.1016/j.bmc.2022.116612
32. Nie JP, Qu ZN, Chen Y, Chen JH, Jiang Y, Jin MN, et al. Discovery and anti-diabetic effects of novel isoxazole based flavonoid derivatives. Fitoterapia. 2020;142:104499. https://doi.org/10.1016/j.fitote.2020.104499

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1. Kadam HK, Salkar K, Naik AP, Naik MM, Salgaonkar LN, Charya, L, et al. Silica supported synthesis and quorum quenching ability of isoxazolones against both gram positive and gram negative bacterial pathogens. Chemistry Select. 2021;6(42):11718-28. https://doi.org/10.1002/slct.202101798

2. Hushare VJ, Rajput PR. Synthesis, characterization and antimicrobial activity of some novel isoxazoles. Rasayan J Chem. 2012;5(1):121-6.

3. Arya GC, Kaur K, Jaitak V. Isoxazole derivatives as anticancer agent: a review on synthetic strategies, mechanism of action and SAR studies. Eur J Med Chem. 2021;221:113511. https://doi.org/10.1016/j.ejmech.2021.113511

4. Baltenneck J, Reverchon S, Hommais F. Quorum sensing regulation in phytopathogenic bacteria. Microorganisms. 2021;9(2):239. https://doi.org/10.3390/microorganisms9020239

5. Yan C, Li X, Zhang G, Zhu Y, Bi J, Hao H, Hou H. Quorum sensing-mediated and growth phase-dependent regulation of metabolic pathways in Hafnia alvei H4. Front Microbiol. 2021;12:567942. https://doi.org/10.3389/fmicb.2021.567942

6. Paluch E, Rewak-Soroczy?ska J, J?drusik I, Mazurkiewicz E, Jermakow KJAM. Prevention of biofilm formation by quorum quenching. Appl Micrbiol Biotechnol. 2020;104:1871-1881. https://doi.org/10.1007/s00253-020-10349-w

7. Wright PP, Ramachandra SS. Quorum sensing and quorum quenching with a focus on cariogenic and periodontopathic oral biofilms. Microorganisms. 2022;10(9):1783. https://doi.org/10.3390/microorganisms10091783

8. Preda VG, S?ndulescu O. Communication is the key: biofilms, quorum sensing, formation and prevention. Discov. 2019;7(3):e100. https://doi.org/10.15190/d.2019.13

9. Zhou L, Zhang Y, Ge Y, Zhu X, Pan J. Regulatory mechanisms and promising applications of quorum sensing-inhibiting agents in control of bacterial biofilm formation. Front Microbiol. 2020;11:589640. https://doi.org/10.3389/fmicb.2020.589640

10. Li T, Mei Y, He B, Sun X, Li J. Reducing quorum sensing-mediated virulence factor expression and biofilm formation in hafnia alvei by using the potential quorum sensing inhibitor L-carvone. Front Microbiol. 2019;9:3324. https://doi.org/10.3389/fmicb.2018.03324

11. Al-Shabib NA, Husain FM, Hassan I, Khan MS, Ahmed F, Qais FA, et al. Biofabrication of zinc oxide nanoparticle from Ochradenus baccatus leaves: broad-spectrum antibiofilm activity, protein binding studies, and in vivo toxicity and stress studies. J Nanomater. 2018;2018:8612158. https://doi.org/10.1155/2018/8612158

12. Richards C, O'Connor N, Jose D, Barrett A, and Regan F. Selection and optimization of protein and carbohydrate assays for the characterization of marine biofouling. Anal Methods. 2020;12(17):2228-36. https://doi.org/10.1039/D0AY00272K

13. Naik MM, Naik SP, Dubey SK, Bhat C, Charya LSJ. Enhanced exopolysaccharide production and biofilm forming ability in methicillin resistant Staphylococcus sciuri isolated from dairy in response to acyl homoserine lactone (AHL). Food Sci Technol. 2018;55:2087-94. https://doi.org/10.1007/s13197-018-3123-0

14. Singh VK, Mishra A, and Jha B. 3-Benzyl-hexahydro-pyrrolo [1, 2-a] pyrazine-1, 4-dione extracted from Exiguobacterium indicum showed anti-biofilm activity against Pseudomonas aeruginosa by attenuating quorum sensing. Front Microbiol. 2019;10:1269. https://doi.org/10.3389/fmicb.2019.01269

15. Nithya C, Begum MF, Pandian SK. Marine bacterial isolates inhibit biofilm formation and disrupt mature biofilms of Pseudomonas aeruginosa PAO1. Appl Microbiol Biotechnol. 2010;88(1):341-58. https://doi.org/10.1007/s00253-010-2777-y

16. Trott O, Olson AJ. AutoDock vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J Comput Chem. 2010;31(2):455-61. https://doi.org/10.1002/jcc.21334

17. Laskowski RA, Swindells MB. LigPlot+: multiple ligand-protein interaction diagrams for drug discovery. J Chem Inf Model. 2011;51(10):2778-86. https://doi.org/10.1021/ci200227u

18. Myszka K, and Czaczyk K. Characterization of adhesive exopolysaccharide (EPS) produced by Pseudomonas aeruginosa under starvation conditions. Curr Microbiol. 2009;58:541-6. https://doi.org/10.1007/s00284-009-9365-3

19. Mina IR, Jara NP, Criollo JE, Castillo JA. The critical role of biofilms in bacterial vascular plant pathogenesis. Plant Pathol J. 2019;68(8):1439-47. https://doi.org/10.1111/ppa.13073

20. Husain FM, Ahmad I, Al-Thubiani AS, Abulreesh HH, AlHazza IM, Aqil F. Leaf extracts of Mangifera indica L. Inhibit quorum sensing- regulated production of virulence factors and biofilm in test bacteria. Front Microbiol. 2017;8:727. https://doi.org/10.3389/fmicb.2017.00727

21. Fong J, Mortensen KT, Nørskov A, Qvortrup K, Yang L, Tan CH, et al. Itaconimides as novel quorum sensing inhibitors of Pseudomonas aeruginosa. Front Cell Infect. 2019;8:443. https://doi.org/10.3389/fcimb.2018.00443

22. Dincer S, Uslu FM, Delik A. Antibiotic resistance in biofilm. In: Dincer S, Ozdenefe MS, Arkut A, eds. Bacterial Biofilms. London: IntechOpen; 2020. pp. 135-48. https://doi.org/10.5772/intechopen.92388

23. Li Y-H, Tian X. Quorum sensing and bacterial social interactions in biofilms. Sensors. 2012;12(3):2519-38. https://doi.org/10.3390/s120302519

24. Thi MTT, Wibowo D, Rehm BH. Pseudomonas aeruginosa biofilms. Int J Mol Sci. 2020;21(22):8671. https://doi.org/10.3390/ijms21228671

25. Idrees M, Sawant S, Karodia N, Rahman A. Staphylococcus aureus biofilm: morphology, genetics, pathogenesis and treatment strategies. Int J Environ Res Public Health. 2021;18(14):7602. https://doi.org/10.3390/ijerph18147602

26. Joshi JR, Khazanov N, Senderowitz H, Burdman S, Lipsky A, Yedidia I. Plant phenolic volatiles inhibit quorum sensing in pectobacteria and reduce their virulence by potential binding to ExpI and ExpR proteins. Sci Rep. 2016;6(1):38126. https://doi.org/10.1038/srep38126

27. Ha NT, Minh TQ, Hoi PX, Thuy NTT, Furuya N, Long HH. Biological control of potato tuber soft rot using N-acyl-L-homoserine lactone-degrading endophytic bacteria. Curr Sci. 2018;115(10):1921-7. https://doi.org/10.18520/cs/v115/i10/1921-1927

28. Mori Y, Inoue K, Ikeda K, Nakayashiki H, Higashimoto C, Ohnishi K, et al. The vascular plant?pathogenic bacterium R alstonia solanacearum produces biofilms required for its virulence on the surfaces of tomato cells adjacent to intercellular spaces. Mol Plant Pathol. 2016;17(6):890-902. https://doi.org/10.1111/mpp.12335

29. Lowe-Power TM, Khokhani D, Allen C. How Ralstonia solanacearum exploits and thrives in the flowing plant xylem environment. Trends Microbiol. 2018;26(11):929-42. https://doi.org/10.1016/j.tim.2018.06.002

30. Kostylev M, Kim DY, Smalley NE, Salukhe I, Greenberg EP, Dandekar AA. Evolution of the Pseudomonas aeruginosa quorum-sensing hierarchy. Proc Nat Acad Sci. 2019;116(14):7027-32. https://doi.org/10.1073/pnas.1819796116

31. Kushwaha PK, Srivastava KS, Kumari N, Kumar R, Mitra D, Sharon A. Synthesis and anti-HIV activity of a new isoxazole containing disubstituted 1, 2, 4-oxadiazoles analogs. Bioorg Med Chem. 2022;56:116612. https://doi.org/10.1016/j.bmc.2022.116612

32. Nie JP, Qu ZN, Chen Y, Chen JH, Jiang Y, Jin MN, et al. Discovery and anti-diabetic effects of novel isoxazole based flavonoid derivatives. Fitoterapia. 2020;142:104499. https://doi.org/10.1016/j.fitote.2020.104499